A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.

Automated summary

We report a medium-throughput drug-screening platform based on organotypic cultures that evaluates inhibitors against metastases growing in situ. Through this approach applied to brain metastasis, vulnerabilities were identified and a blood-brain barrier permeable HSP90 inhibitor was found to be effective against mouse and human brain metastases. In situ proteomic analysis revealed a novel molecular program in brain metastasis and potential biomarkers of poor prognosis and resistance mechanisms. This study validates METPlatform as a potent resource for metastasis research and personalized management of metastatic disease.